Biomedical subjects

T M Morgan

Publications and source records attributed to T M Morgan.

At least 55 records · Page 3Linked to original sources

PubMed1992

Imidazole-5-acrylic acids: potent nonpeptide angiotensin II receptor antagonists designed using a novel peptide pharmacophore model.

A series of novel nonpeptide angiotensin II receptor antagonists containing a substituted (E)-acrylic acid has been developed. The overlay of 1, an imidazole-5-acetic acid found in the patent literature, on a novel pharmacophore model of AII suggested that extension of the acid side chain and attachment of a second aryl residue to mimic the C-terminal phenylalanine region of AII would lead to increased activity. A study of extended acid side chains at C-5 of the imidazole nucleus led to the discovery of the (E)-acrylic acid 5 as a promising starting point for further exploration. As predicted by the modeling, substitution of a benzyl group on the acrylic acid side chain to mimic the phenylalanine gave increased potency. An extensive study of the SAR of the newly introduced aromatic ring revealed that electron-rich heteroaryl rings provided improved activity, most notably in the in vivo rat models. Compound 40, (E)-3-[2-butyl-1- [(2-chlorophenyl)methyl]imidazol-5-yl]-2-[(2-thienyl)methyl]-2- propenoic acid, has been shown to be a potent, competitive, and orally active small molecule AT-1 receptor antagonist. It exhibits a 2 orders of magnitude increase in binding affinity and a 10-fold improvement in in vivo potency as compared to compound 1 and represents an important milestone in the development of even more potent nonpeptide angiotensin II receptor antagonists.

Acrylates↗

PubMed1992

Pseudophakic retinal detachments. Anatomic and visual results.

Retinal reattachment rates and visual results were analyzed in 227 consecutive primary pseudophakic rhegmatogenous retinal detachments. The overall anatomic reattachment rate was 90%, with no significant difference between the anterior chamber (AC) and posterior chamber intraocular lens groups. Visual results were significantly worse in the AC lens group (P less than 0.05). Negative prognostic indicators for reattachment included age greater than 65 years, poorer preoperative vision, larger extent of the retinal detachment, inability to identify a retinal break, longer duration of symptoms before presentation, and grades C or D proliferative vitreoretinopathy (P less than 0.05). In addition to the above factors, eyes with AC reaction, AC lenses, and macular detachment had a poorer visual prognosis.

Adult↗

PubMed1990

How best to teach women breast self-examination. A randomized controlled trial.

OBJECTIVE: To compare three methods for teaching breast self-examination. DESIGN: Randomized controlled trial with factorial design. SETTING: A general medicine group practice in a university hospital. PATIENTS: Continuing-care patients from 40 to 68 years of age. Of 456 eligible women, 156 refused participation, 300 were randomly assigned, 269 completed assigned interventions, and 260 completed the post-test 1 year later. INTERVENTIONS: One third of patients received nurse instruction stressing tactile skills (Mammacare group) (Mammatech Corporation, Gainesville, Florida); one third, traditional nurse instruction emphasizing technique (traditional group); and one third, no nurse instruction (control group). Half of each group received physician encouragement. MEASUREMENTS AND MAIN RESULTS: One year later, women in the Mammacare group found more lumps (mean, 57%; 95% CI, 54% to 60%) in manufactured breast models than did those in the traditional (mean, 47%; CI, 44% to 51%) and control (mean, 45%; CI, 42% to 48%) groups. Lump detection specificity was unaffected. Self-reported examination frequency rose in all groups, to 5.1 times per 6 months in the traditional group, 4.2 in the Mammacare group, and 3.9 in the control group. Physician encouragement did not improve sensitivity, specificity, or overall frequency. Women in the Mammacare group used more of seven examination techniques (4.9) than did those in the traditional (3.9) or control (3.2) groups (P less than 0.001). No group increased health care use or reported more overall worry about breast cancer. CONCLUSIONS: Mammacare instruction resulted in more long-term improved lump detection and examination technique use than did traditional instruction or physician encouragement. Breast self-examination instruction should emphasize lump detection skills.

Adult↗

PubMed1990

The effects of estrogen, progesterone, and tamoxifen alone and in combination with cytotoxic agents against human ovarian carcinoma in vitro.

The effects of estradiol (E), medroxyprogesterone acetate (MPA), and tamoxifen (TAM) on the growth of a human ovarian carcinoma cell line, BG-1, were evaluated using a tumor clonogenic assay (HTCA). BG-1 contains significant quantities of estrogen and progesterone receptors. Growth inhibition by TAM and growth stimulation by MPA were demonstrated using continuous drug exposure. Estradiol resulted in a marginal increase in colony formation. With each of these three drugs, the greatest response occurred in the larger colonies (generally greater than or equal to 60 microns). Combinations of each of these three steroidal agents with three different cytotoxic drugs were studied in the HTCA. Synergistic activities were produced with TAM combined with either cisplatin or doxorubicin. Additive effects were seen with TAM and cyclophosphamide. Although predominantly additive or synergistic, the effects were variable with MPA and all three cytotoxic agents. Combinations of estradiol with cytotoxic agents were no more active than the cytotoxics alone. These findings indicate a biological rationale for hormonal manipulation as therapy in ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Bromodeoxyuridine incorporation into DNA of human leukemia cells is not concentration dependent.

Leukemia blasts isolated from bone marrow aspirates of 44 adults with acute leukemia were incubated for 1 h with 0.008-32 microM bromodeoxyuridine (Brd-Urd). After dual labeling with monoclonal anti-BrdUrd antibodies and propidium iodide, the cells were analyzed by flow cytometry. Percent labeled cells and intensity of labeling were similar over concentrations of BrdUrd ranging from 0.8-32 microM--a 40-fold range. Therefore, despite potential interpatient variability in nucleoside pharmacokinetics, commonly used doses of BrdUrd which are intended to achieve steady-state plasma concentrations in the 8.0 microM range can be expected to provide a reliable estimate of the S-phase fraction.

Antibodies, Monoclonal↗

PubMed1990

Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys.

Studies of both human and nonhuman primates show an inverse relationship between high-density lipoprotein (HDL) cholesterol concentrations and coronary artery atherosclerosis. For this reason, there has been concern that the HDL cholesterol-lowering effect of oral contraceptives might exacerbate coronary artery atherosclerosis. We studied three groups of adult female cynomolgus macaques fed a moderately atherogenic diet: a control group, a group given ethinyl estradiol and norgestrel, and another group given ethinyl estradiol and ethynodiol diacetate. Norgestrel and ethynodiol diacetate, co-administered with ethinyl estradiol, lowered the plasma concentrations of HDL cholesterol. However, the extent of coronary artery atherosclerosis was lessened by both contraceptives, especially among females at high risk based on their plasma lipid profiles.

Animals↗

PubMed1989

The predictive value of progesterone receptor levels in endometrial cancer.

Recent reports have suggested that the presence of progesterone receptor correlates with other well known predictors of a favorable outcome for endometrial cancer patients. To test this hypothesis, we reviewed the records of 154 patients who had undergone a hysterectomy for adenocarcinoma of the endometrium, and pelvic irradiation if poor prognostic factors were present. The 3 year disease-free survival for all clinical Stage I patients was 80%. Patients with progesterone receptor levels greater than or equal to 100 had a 3 year disease-free survival of 93% compared with only a 36% 3 year disease-free survival for patients with progesterone receptor less than 100 (p less than .0001, log rank test). To determine whether elevated progesterone receptor was an independent prognostic factor for disease-free survival in endometrial cancer, or just correlated with the other well-known predictors, bivariate and multivariate analyses were conducted. Our results indicate the progesterone receptor levels are the single most important prognostic indicator of 3 year disease-free survival in clinical Stage I endometrial cancer, with only cervical involvement and peritoneal cytology being significant prognostic variables after adjusting for progesterone receptor levels.

Analysis of Variance↗

PubMed1989

Low-dose ara-C therapy for acute myelogenous leukemia in elderly patients.

Forty-four evaluable patients with untreated acute myelogenous leukemia received twice-daily subcutaneous injections of low-dose ara-C (10 mg/m2) for less than or equal to 42 days. The median age was 72 years (range 53-87); 42 of 44 patients were greater than or equal to age 60. Ten patients (23%) had complete responses with a median duration of 9.9 months. Median survival was 3 months (range 0.6-31.2+) for all patients, and 19.5 (range 7.9-31.2+) for patients who attained complete responses. Cytoreduction occurred slowly with low-dose ara-C and five of ten patients who achieved complete remission did not develop marrow aplasia. Toxicity was predominantly related to infections associated with granulocytopenia. Nonhematologic toxicity was limited. Low-dose ara-C as used in this trial results in a complete response rate and a duration of response similar to those achieved with other treatments in elderly patients, but with reduced toxicity.

Aged↗

PubMed1988

Ambulatory 24-hour esophageal pH monitoring. Reproducibility and variability of pH parameters.

If 24-hour esophageal pH monitoring is to be a useful diagnostic tool, it must reliably discriminate gastroesophageal reflux patients despite daily variations in distal esophageal acid exposure. To address this issue, we studied 53 subjects (14 healthy normals, 14 esophagitis patients, and 25 patients with atypical symptoms) with two ambulatory pH tests performed within 10 days of each other. Intrasubject reproducibility of 12 pH parameters to discriminate the presence of abnormal acid reflux was determined. As a group, the parameters of percent time with pH less than 4 (total, upright, recumbent) were most reproducible (80%). Therefore, a subject was defined as having gastroesophageal reflux disease if at least one of these three values were abnormal. Intrasubject reproducibility for the diagnosis of reflux disease was 89% for the entire sample. Among subsets, the reproducibility was 93% for the normals and esophagitis patients and 84% for the atypical symptom patients. Total percent time with pH less than 4 was the single most discriminate pH parameter (85%) and nearly equaled that of the three combined parameters (89%). The intrasubject variability of this parameter was determined by the mean +/- 2 SD of the relative differences between the two test results for all 53 subjects. Total percent time with pH less than 4 may vary between tests by a factor of 3.2-fold or less (218% higher to 69% lower). We conclude: (1) ambulatory 24-hr esophageal monitoring is a reproducible test for the diagnosis of gastroesophageal reflux disease; and (2) the large intrastudy variability in 24-hr total acid exposure may limit this test's usefulness as a measurement of therapeutic improvement.

Adult↗

PubMed1988

Analysis of duration of response: a problem of oncology trials.

Comparing response durations between treatment groups in a randomized clinical trial can be inappropriate and give misleading results concerning the relative durability of responses. Due to patient variability, the treatment producing more responses will usually also have responsive patients of poorer prognosis. A treatment that increases the probability and duration of a response can appear to produce responses of shorter duration based on an analysis of duration of response. Alternative procedures are discussed.

Antineoplastic Agents↗

PubMed1988

Circulating antibodies and antigens in Presbytis monkeys infected with the filarial parasite Wuchereria bancrofti.

Levels of circulating filarial antigen, and humoral antibody to other defined antigenic targets, were measured over the course of experimental infection of three Presbytis cristatus monkeys with Wuchereria bancrofti. Circulating antigen levels, measured with an anti-phosphorylcholine monoclonal antibody, varied widely although all animals were positive for some period of the infection. Circulating antigen levels tended to be inversely related to the titre of anti-phosphorylcholine antibody, and this trend was maintained even following acid dissociation and inactivation of immune complexed host antibody. Other antibody specificities were measured by Western blotting against somatic proteins and immunoprecipitation of surface antigens. Amongst somatic antigens, targets between 14,000 and 200,000 daltons were recognised by monkey antibodies, but no correlation with infection status could be discerned. Likewise when measuring the response to the 29,000 dalton major adult surface glycoprotein, one animal produced a rapid response but the others did not recognise it until late in infection. In general, the experimental findings are characterised by wide variability between individuals, as may perhaps be expected in a primate host for a human spectral disease.

Animals↗

PubMed1987

Effects of psychological therapy on pain behavior of rheumatoid arthritis patients. Treatment outcome and six-month followup.

A randomized clinical trial was performed to evaluate a psychological treatment intervention and a social support program, compared with a control program in which no adjunct treatment was rendered, and their effects upon pain behavior, affect, and disease activity of 53 patients with rheumatoid arthritis. The psychological intervention produced significant reductions in patients' pain behavior and disease activity at posttreatment. Significant reductions were also observed in trait anxiety at posttreatment and 6-month followup. Relaxation training may have been the most important component of the psychological intervention. The social support program produced a significant reduction in trait anxiety only at posttreatment. This is the first well-controlled study to demonstrate reduced pain behavior, disease activity, and trait anxiety following psychological treatment.

Adult↗

PubMed1987

Optimal restricted two-stage designs.

The fixed sample p value at the final stage of a group sequential design may be "significant" while the overall p value for the trial as designed may be "nonsignificant." This can lead to confusion in reporting and interpreting final stage results. Two-stage designs are presented that allow acceptance, rejection, or continuation at the first stage while retaining the fixed sample critical value at the second stage. The designs are optimized under this restriction to minimize the expected sample size under the null hypothesis, the expected sample size under a specific alternative hypothesis, or the maximum expected sample size. These restricted designs are almost fully efficient when compared to optimal unrestricted two-stage designs. Additionally, one can interpret the results of hypothesis tests at the final stage as though a fixed sample design had been used. Examples are given which illustrate the use of these restricted plans in the design and analysis of clinical trials.

Biometry↗

PubMed1987

Nonparametric estimation of duration of accrual and total study length for clinical trials.

Nonparametric estimates for all possible values of accrual duration and total study length required to achieve a specified power and level of significance are given assuming a proportional hazards model comparing two treatment groups. Based on data from a previous representative clinical trial, the nonparametric maximum likelihood estimate of total study length and its asymptotic distribution are derived as functions of accrual duration. An example using this technique is given for designing a clinical trial comparing two adjuvant chemotherapy regimens for large bowel cancer.

Biometry↗

PubMed1986

Endometrial adenocarcinoma. A multiparameter clinicopathologic analysis including the DNA profile and the sex steroid hormone receptors.

With endometrial adenocarcinoma, several factors, such as stage and histologic grade, are well recognized as having prognostic significance. Other variables, e.g., nuclear grade, probably are also important clinically. A preliminary investigation of the prognostic value of the ploidy, cell cycle kinetics, and sex steroid receptor contents of these tumors has been conducted and compared with more conventional prognostic factors such as stage, grades, and depth of invasion. As analyzed by flow cytometry, the proliferative activities of the carcinomas were significantly associated with prognosis. Tumors with lower levels of proliferative activity were related to improved survivals. Two thirds of the carcinomas were diploid; ploidy did not carry prognostic weight in the series. Both the estrogen and progesterone receptor status were related to survival. Patients whose tumors were positive for these receptors had a better prognosis than did those in which the receptors were not present in significant quantities.

Adenocarcinoma↗

PubMed1986

Antigenic characterization of adult Wuchereria bancrofti filarial nematodes.

Adult Wuchereria bancrofti were recovered from infected Presbytis cristatus monkeys and radio-isotope labelled extrinsically with 125I and in vitro with [35S]methionine. 125I labelling of the surface of adult W. bancrofti permitted a comparison between the major surface antigens of this species and those from the related lymphatic filariae, Brugia malayi and B. pahangi. All species bear a prominent Mr 29,000 surface antigen but among the differences observed were the strongly labelled molecules with Mr 58,000 and 67,000 in W. bancrofti which are extremely faint in the Brugia species. The [35S]methionine label was effectively incorporated into somatic parasite proteins in vitro although it was not possible to identify any secreted proteins in this way. The antigenicity of these products was investigated using a variety of sera from homologous and heterologous infections and the immunoprecipitation patterns highlighted particular differences between somatic proteins of male and female worms. One secreted antigen was detected, however, by virtue of its phosphorylcholine epitopes, in the culture medium of mixed adult worms; medium from male W. bancrofti adults was negative although homogenates of either sex of adult W. bancrofti were strongly positive in the same system.

Animals↗

PubMed1986

Analysis of the relationships of the ploidy and cell cycle kinetics to differentiation and the female sex steroid hormone receptors in adenocarcinoma of the endometrium.

Flow cytometry was used to evaluate proliferative activity and ploidy status in 21 endometrial adenocarcinomas. These data were compared with their histologic and nuclear grades and their estrogen and progesterone receptor contents. Proliferative activity was significantly related to histologic and nuclear grades and the progesterone receptor status but not to the estrogen receptor status. Unlike the majority of solid human malignant neoplasms, only seven tumors were aneuploid, the remainder being diploid. Ploidy was not significantly associated with either grading system, receptor status, or the proliferative index.

Adenocarcinoma↗

PubMed1986

Combination vincristine and VP-16-213: evaluation of drug sequence.

The combination of vincristine and VP-16-213 has been found to have synergistic antitumor activity in a murine system in vivo when the sequence of drug administration was vincristine followed by VP-16-213. To investigate the potential influence of drug scheduling on this synergistic combination, the reverse sequence of drug administration was evaluated. DBA/2 mice were inoculated with 10(6) P-388 murine leukemia cells, after which saline only, VP-16-213 only, vincristine only, or VP-16-213 followed at various time intervals by vincristine, were administered. Probable cure (survival greater than 60 days) was observed in 0/20, 0/20, 0/120, and 46/115 (40%), respectively (p less than 0.001). The proportion of animals attaining probable cure was greatest in the group receiving vincristine 4-72 hours after VP-16-213 (40-50%). Similar results had been obtained previously with the reverse drug sequence. In this animal model, the synergistic antitumor activity of vincristine and VP-16-213 does not appear to be schedule-dependent with respect to the sequence of drug administration.

Animals↗